The long term goal of our research program is characterization of interaction energetics for biological macromolecule-ligand reactions. The work will emphasize use of microcalorimetry for direct measurement of heats of reaction. The calorimetric measurements will be accompanied by evaluation of equilibrium constants, to permit calculation of delta G and delta S, as well as on delta H and delta Cp. Equilibrium constants will be obtained from analysis of binding data for the best equilibrium model supported by the data. Our research will be confined initially to protease- ligand systems because of the large amount of information already available concerning chemical modifications, purification, reaction kinetics, and X-ray crystallographic structure. These additional sources of information are essential for interpretation of thermodynamic data at the molecular level in terms of residue interactions and solvent effects; knowledge of binding site geometry must be known to permit assignment of energy contributions. Information gained by studying proteases will be pertinent to the properties of many other proteins, but will be of direct use in human nutrition, blood chemistry, and in reproduction processes, where proteases are known to have direct roles.